Gender differences in management and outcome in non-ST-elevation acute coronary syndrome

Objective

To study gender differences in management and outcome in patients with non‐ST‐elevation acute coronary syndrome.

Design, setting and patients

Cohort study of 53 781 consecutive patients (37% women) from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS‐HIA), with a diagnosis of either unstable angina pectoris or non‐ST‐elevation myocardial infarction. All patients were admitted to intensive coronary care units in Sweden, between 1998 and 2002, and followed for 1 year.

Main outcome measures

Treatment intensity and in‐hospital, 30‐day and 1‐year mortality.

Results

Women were older (73 vs 69 years, p<0.001) and more likely to have a history of hypertension and diabetes, but less likely to have a history of myocardial infarction or revascularisation. After adjustment, there were no major differences in acute pharmacological treatment or prophylactic medication at discharge.Revascularisation was, however, even after adjustment, performed more often in men (OR 1.15; 95% CI, 1.09 to 1.21). After adjustment, there was no significant difference in in‐hospital (OR 1.03; 95% CI, 0.94 to 1.13) or 30‐days (OR 1.07; 95% CI, 0.99 to 1.15) mortality, but at 1 year being male was associated with higher mortality (OR 1.12; 95% CI, 1.06 to 1.19).

Conclusion

Although women are somewhat less intensively treated, especially regarding invasive procedures, after adjustment for differences in background characteristics, they have better long‐term outcomes than men.Since the beginning of the 1990s there have been numerous studies on gender differences in management of acute coronary syndromes (ACS). Many earlier studies,^{1,2,3,4,5,6,7,8} but not all,⁹ found that women were treated less intensively in the acute phase. In some of the studies, after adjustment for age, comorbidity and severity of the disease, most of the differences disappeared.^6,7 There is also conflicting evidence on gender differences in evidence‐based treatment at discharge.^{1,3,5,6,8,10,11}After acute myocardial infarction (AMI), a higher short‐term mortality in women is documented in several studies.^{2,5,6,7,12,13,14} After adjustment for age and comorbidity some difference has usually,^2,5,12,13 but not always,^11,14 remained. On the other hand, most studies assessing long‐term outcome have found no difference between the genders, or a better outcome in women, at least after adjustment.^7,10,13,14 Earlier studies focusing on gender differences in outcome after an acute coronary syndrome have usually studied patients with AMI, including both ST‐elevation myocardial infarction and non‐ST‐elevation myocardial infarction (NSTEMI).^{2,5,6,7,12,13,14} However, the pathophysiology and initial management differs between these two conditions,¹⁵ as does outcome according to gender.^11,16 In patients with NSTEMI or unstable angina pectoris (UAP), women seem to have an equal or better outcome, after adjustment for age and comorbidity.^{1,4,8,11,16,17} Studies on differences between genders, in treatment and outcome, in real life, contemporary, non‐ST‐elevation acute coronary syndrome (NSTE ACS) populations, large enough to make necessary adjustments for confounders, are lacking.The aim of this study was to assess gender differences in background characteristics, management and outcome in a real‐life intensive coronary care unit (ICCU) population, with NSTE ACS.     

Efficacy of Repeat Review with Flexible Spectral Imaging Color Enhancement in Patients with no Findings by Capsule Endoscopy

Background/Aim:The efficacy of flexible spectral imaging color enhancement (FICE) ch. 1 (F1) for the detection of ulcerative lesions and angioectasias in the small intestine with capsule endoscopy (CE) has been reported. In the present study, we evaluated whether F1 could detect incremental findings in patients with no findings in a standard review mode.Results:F1 detected five significant lesions in three patients with overt OGIB; three erosions, one aphtha, and one angioectasia. For nonsignificant lesions, F1 detected 12 red mucosas and 16 red spots. Moreover, 29 patients with 71 findings were considered false positives.Conclusion:F1 detected incremental significant findings in a small percentage of patients with no findings in the standard review mode. In addition, F1 showed many false-positive findings. The incremental effect of a repeated review by F1 in patients with no findings in the first review is limited.Key Words: Capsule endoscopy, flexible spectral imaging color enhancement, obscure gastrointestinal bleeding, repeat review, small intestinal lesionFlexible spectral imaging color enhancement (FICE), an image-enhanced endoscopy (IEE) technique, has been used widely in gastroscopy and colonoscopy.[1,2] FICE depends on optical filters and the use of spectral estimation technology to reconstruct images at different wavelengths based on images from white-light endoscopy. It has been reported that it improves the visualization of both neoplastic and non-neoplastic lesions in gastroscopy and colonoscopy.[3,4,5]Capsule endoscopy (CE) has become an important examination of the small intestine.[6] The efficacy of CE for small intestinal diseases has been reported.[7,8,9,10,11] CE has demonstrated efficacy for patients with obscure gastrointestinal bleeding (OGIB). It can detect various kinds of disease states such as tumors, polyps, angioectasias, ulcers, and erosions.Rapid 6.5 (Given Imaging Ltd., Yoqneam, Israel), a CE reading system, includes FICE.[12] Several studies have shown the effects of FICE in CE.[13,14,15,16,17,18,19,20] In a previous study, we found that FICE Ch. 1 (F1) detected a larger number of ulcerative lesions and angioectasias in the small intestine compared to a standard review.[16] However, little is known about the impact of FICE on CE in patients, with no findings in the standard mode CE. In the present study, we investigated whether F1 could detect incremental findings in patients with no findings in the standard review mode.     

Bone mineral density in patients with hand osteoarthritis compared to population controls and patients with rheumatoid arthritis

Objectives

Several studies have revealed increased bone mineral density (BMD) in patients with knee or hip osteoarthritis, but few studies have addressed this issue in hand osteoarthritis (HOA). The aims of this study were to compare BMD levels and frequency of osteoporosis between female patients with HOA, rheumatoid arthritis (RA) and controls aged 50–70 years, and to explore possible relationships between BMD and disease characteristics in patients with HOA.

Methods

190 HOA and 194 RA patients were recruited from the respective disease registers in Oslo, and 122 controls were selected from the population register of Oslo. All participants underwent BMD measurements of femoral neck, total hip and lumbar spine (dual‐energy x ray absorptiometry), interview, clinical joint examination and completed self‐reported questionnaires.

Results

Age‐, weight‐ and height‐adjusted BMD values were significantly higher in HOA versus RA and controls, the latter only significant for femoral neck and lumbar spine. The frequency of osteoporosis was not significantly different between HOA and controls, but significantly lower in HOA versus RA. Adjusted BMD values did not differ between HOA patients with and without knee OA, and significant associations between BMD levels and symptom duration or disease measures were not observed.

Conclusion

HOA patients have a higher BMD than population‐based controls, and this seems not to be limited to patients with involvement of larger joints. The lack of correlation between BMD and disease duration or severity does not support the hypothesis that higher BMD is a consequence of the disease itself.Osteoporosis is recognised as a frequent complication to rheumatoid arthritis (RA).¹ Osteoarthritis (OA) is the most frequent rheumatic joint disease, and contrary to the situation in RA, several studies have revealed increased bone mineral density (BMD) in patients with knee or hip OA, even if the results have not been consistent in all studies.^{2,3,4,5,6,7,8,9,10} The hand is a frequent site of peripheral joint involvement in OA. However, a limited number of studies have addressed the issue of osteoporosis in hand osteoarthritis (HOA), and the results from these few studies have been inconsistent regarding levels of BMD compared with controls.^{8,9,10,11,12,13,14,15}OA has generally been considered as a cartilage disease characterised by slow progressive degeneration of articular cartilage due to “wear and tear” mechanisms. However, there is increasing evidence that abnormalities in the subchondral bone and systemic factors may contribute to the pathophysiological process. Studies of subchondral bone have revealed alterations in microstructure including increased BMD. This local increase in BMD in OA joints may be a consequence of reduced shock absorption in joints with degenerated cartilage,⁵ or on the contrary, thickening and stiffening of the subchondral bone with increased BMD may lead to development of OA.¹⁶ However, elevated BMD levels at sites remote from the arthritic process cannot be explained by local biomechanical factors, and the question of whether primary OA rather is a systemic bone disease has been raised.¹⁷ Systemic changes in subchondral bone could be explained by genetic factors, hormonal influences, vitamin D concentrations, growth factors or activity of bone‐forming cells.^{15,18,19,20,21} Better knowledge about the relationship between BMD and HOA may contribute to the understanding of the pathogenesis of OA.Disease registers of patients with RA²² and HOA²³ have been established in the city of Oslo. We have previously compared BMD levels in a cohort of RA patients from the Oslo RA Register (ORAR) and healthy controls.²⁴ The current study was designed to compare levels of BMD and the frequency of osteoporosis between patients with HOA, RA and controls. A second aim was to explore possible relationships between BMD levels and disease characteristics in patients with HOA.     

Microscopic measurement of inflammation in synovial tissue: inter-observer agreement for manual quantitative, semiquantitative and computerised digital image analysis

Objectives

To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.

Methods

Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman''s Rho and intraclass correlation coefficients (ICCs).

Results

Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.

Conclusion

Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.Microscopic measurement of inflammation in synovial tissue is employed globally by centres working in the field of arthritis research.¹ Adequate and comparable synovial tissue can be safely obtained using blind‐needle biopsy or rheumatological arthroscopy.^2,3,4 In the acquired samples, various parameters may be examined, including cell populations, vascularity, cytokines and adhesion molecules. In rheumatoid arthritis (RA), many of these have been found to relate to disease activity, severity, outcome, and to exhibit a change after treatment with corticosteroids, disease‐modifying antirheumatic drugs (DMARDs) and biological therapy.^{5,6,7,8,9,10,11,12,13,14,15}Several analysis techniques have been employed to measure these parameters. Semiquantitative analysis is a relatively quick method and therefore may facilitate examining large quantities of tissue.⁷ Quantitative analysis is time‐consuming but more sensitive than semiquantitative scoring to change in individual patients.¹⁶ It has been shown in previous studies that these methods can reflect overall joint inflammation when applied to relatively limited amounts of synovial tissue, even though inflammation may differ widely between individual sites in a single joint.^17,18,19 Computerised digital image analysis has been applied more recently in this area and has been shown to correlate well with conventional methods of measurement.^20,21,22This multi‐centre study was undertaken to standardise and validate the methods mentioned previously by evaluating inter‐observer agreement between multiple examiners in the measurement of selected parameters of inflammation in RA synovial tissue by manual quantitative, semiquantitative and computerised image analysis.     

A Systematic Review on the Safety and Effectiveness of yttrium-90 Radioembolization for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Background/Aim:Over the past two decades, several advances have been made in the management of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). Yttrium-90 (⁹⁰Y) radioembolization has recently been made a treatment option for patients with HCC and PVTT. However, there is still a need to systematicly evaluate the outcomes of ⁹⁰Y radioembolization for HCC and PVTT. We aimed to assess the safety and effectiveness of ⁹⁰Y radioembolization for HCC and PVTT. We performed a systematic review of clinical trials, clinical studies, and abstracts from conferences that qualified for analysis.Results:A total of 14 clinical studies and three abstracts from conferences including 722 patients qualified for the analysis. The median length of follow-up was 7.2 months; the median time to progression was 5.6 months, and median disease control rate was 74.3%. Radiological response data were reported in five studies, and the median reported value of patients with complete response, partial response, stable disease, and progressive disease were 3.2%, 16.5%, 31.3%, and 28%, respectively. The median survival was 9.7 months for all patients, including the median overall survival (OS) were 12.1, 6.1 months of Child-Pugh class A and B patients, and the median OS were 6.1, 13.4 months of main and branch PVTT patients, respectively. The common toxicities were fatigue, nausea/vomiting, abdominal pain, mostly not requiring medical intervention needed no medication intervention.Conclusions:⁹⁰Y radioembolization is a safe and effective treatment for HCC and PVTT.Key Words: Hepatocellular carcinoma, portal vein tumor thrombosis, radioembolization, toxicity, yttrium-90Portal vein tumor thrombosis (PVTT) occurs in a substantial portion of hepatocellular carcinoma (HCC) patients and in approximately 10%–40% of patients at diagnosis.[1,2] PVTT has a profound adverse effect on prognosis, with the median survival time of patients who have unresectable HCC with PVTT being significantly reduced (2–4 months) compared with those without PVTT (10–24 months).[1,3] The presence of PVTT also limits the treatment options, with HCC treatment guidelines often considering PVTT a contraindication for transplantation, curative resection, and transarterial chemoembolization (TACE).[4,5] Although the presence of PVTT poses a challenging treatment dilemma,[1] many treatments of HCC with PVTT have been reported, including surgical,[2] TACE,[4,5,6,7,8,9] external beam radiotherapy,[10] gamma-knife radiosurgery,[4] TACE combined with endovascular implantation of an iodine-125 seed strand,[11] and transarterial radioembolization.[12] However, the optimal treatment for patients with HCC and PVTT remains largely controversial.[7] Yttrium-90 (⁹⁰ Y) radioembolization is a locoregional liver-directed therapy that involves transcatheter delivery of particles embedded with the radioisotope ⁹⁰Y. In addition to obliteration of the arterial blood supply, the ⁹⁰Y results in a 50–150 Gy dose of radiation to the tumor tissue, which results in tumor necrosis, including HCC and PVTT.[13] It was reported that ⁹⁰Y radioembolization is a safe and effective treatment for patients with HCC and PVTT.[6] However, there is still a need to systematically evaluate the outcomes of this treatment modality.The purpose of this study was to comprehensively review the safety and effectiveness of ⁹⁰Y radioembolization for HCC and PVTT.     

The limits of protection by "memory" T cells in Ig-/- mice persistently infected with a gamma-herpesvirus

Can CD4⁺ and CD8⁺ “memory” T cells that are generated and maintained in the context of low-level virus persistence protect, in the absence of antibody, against a repeat challenge with the same pathogen? Although immune T cells exert effective, long-term control of a persistent γ-herpesvirus (γHV68) in Ig^–/– μMT mice, subsequent exposure to a high dose of the same virus leads to further low-level replication in the lung. This lytic phase in the respiratory tract is dealt with effectively by the recall of memory T cells induced by a γHV68 recombinant (M3LacZ) that does not express the viral M3 chemokine binding protein. At least for the CD8⁺ response, greater numbers of memory T cells confer enhanced protection in the M3LacZ-immune mice. However, neither WT γHV68 nor the minimally persistent M3LacZ primes the T cell response to the extent that a WT γHV68 challenge fails to establish latency in the μMT mice. Memory CD4⁺ and CD8⁺ T cells thus act together to limit γHV68 infection but are unable to provide absolute protection against a high-dose, homologous challenge.Along-term debate in the immunology community concerns the importance of antigen persistence for maintaining T cell memory (1–3). The discussion is often confused by different interpretations of the term “memory” (4). If we look at memory simply as the capacity to maintain antigen-specific, “resting” T cell numbers indefinitely, then it seems that the continued presence of the particular MHC class I or class II glycoprotein plus peptide (epitope) is certainly not required (2, 3, 5, 6). However, if memory is used in the sense of the protective immunity that might be the focus of a candidate T cell-based vaccine, then the case that continued (or sporadic) reexposure to the inducing antigen is advantageous could well have merit (7).Acutely activated T cells deal very effectively with a homologous virus challenge (8). On the other hand, the time taken to recall “resting” memory allows an invading organism to become established (9), although the pathogen may either be cleared more rapidly or (for an agent that persists) be held to a lower “set point” (10). Although cytotoxic T cells can be induced very rapidly in vivo (11, 12), their localization to (for example) the respiratory mucosa may be delayed by the need for further activation and proliferation in the lymphoid tissue (13). Could protection be made more immediate by achieving a continuing state of enhanced lymphocyte turnover (14) and activation?The herpesviruses (HVs) provide a natural system for analyzing immunity in the context of controlled virus persistence (15, 16). Vaccination strategies with the γHVs, like Kaposi''s sarcoma virus (HHV8) and Epstein–Barr virus (EBV), can be investigated (17–22) with the murine γ-herpesvirus 68 (γHV68), a virus that has high level sequence homology with HHV8 and a pathogenesis similar to that of EBV (17–19). Respiratory exposure of C57BL/6J (B6) mice to γHV68 induces transient, lytic infection of the respiratory tract and latency in B lymphocytes and macrophages (20, 21). Virus is not normally detected by plaque assay of lung homogenates for >10–12 days after the initial challenge. Genetically disrupted μMT mice that lack both B cells and antibody (Ig^–/–) also clear γHV68 from the lung and show little evidence of latency by infectious center assay (22). However, a more sensitive limiting dilution analysis (LDA) showed that γHV68 persists in macrophages and, perhaps, in other cells from Ig^–/– mice after both i.p. and intranasal (i.n.) challenge (21, 23).The present experiments ask whether the combination of CD4⁺ and CD8⁺ T cell memory (24) in mice infected once with γHV68 (25, 26) protects against superinfection with the same virus. Antibody is, of course, likely to neutralize the majority of input virus in this circumstance (27–29). Therefore, the experiments were done with Ig^–/– μMT mice (30) that had been infected with either WT γHV68 or with a mutant virus (M3LacZ) that causes a normal, lytic infection in the lung, but a much lower level of latency in the lymphoid tissue of Ig^+/+ controls (22). It is also the case that the protective capacity of immune CD4⁺ and CD8⁺ T cells that are maintained where there is the possibility of continued, low level antigen challenge has not (to our knowledge) been analyzed previously for any virus system.     

Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome

Objective

S100A12 is a pro‐inflammatory protein that is secreted by granulocytes. S100A12 serum levels increase during inflammatory bowel disease (IBD). We performed the first study analysing faecal S100A12 in adults with signs of intestinal inflammation.

Methods

Faecal S100A12 was determined by ELISA in faecal specimens of 171 consecutive patients and 24 healthy controls. Patients either suffered from infectious gastroenteritis confirmed by stool analysis (65 bacterial, 23 viral) or underwent endoscopic and histological investigation (32 with Crohn''s disease, 27 with ulcerative colitis, and 24 with irritable bowel syndrome; IBS). Intestinal S100A12 expression was analysed in biopsies obtained from all patients. Faecal calprotectin was used as an additional non‐invasive surrogate marker.

Results

Faecal S100A12 was significantly higher in patients with active IBD (2.45 ± 1.15 mg/kg) compared with healthy controls (0.006 ± 0.03 mg/kg; p<0.001) or patients with IBS (0.05 ± 0.11 mg/kg; p<0.001). Faecal S100A12 distinguished active IBD from healthy controls with a sensitivity of 86% and a specificity of 100%. We also found excellent sensitivity of 86% and specificity of 96% for distinguishing IBD from IBS. Faecal S100A12 was also elevated in bacterial enteritis but not in viral gastroenteritis. Faecal S100A12 correlated better with intestinal inflammation than faecal calprotectin or other biomarkers.

Conclusions

Faecal S100A12 is a novel non‐invasive marker distinguishing IBD from IBS or healthy individuals with a high sensitivity and specificity. Furthermore, S100A12 reflects inflammatory activity of chronic IBD. As a marker for neutrophil activation, faecal S100A12 may significantly improve our arsenal of non‐invasive biomarkers of intestinal inflammation.The etiology of inflammatory bowel disease (IBD) consisting of ulcerative colitis and Crohn''s disease involves complex interactions among susceptibility genes, the environment, and the immune system. These interactions lead to a cascade of events that involve the activation of neutrophils, production of proinflammatory mediators, and tissue damage.¹ As intestinal symptoms are a frequent cause of referrals to gastroenterologists, it is crucial to differentiate between non‐inflammatory irritable bowel syndrome (IBS) and IBD. To date, there is a lack of biological markers to determine intestinal inflammation.^2,3 Therefore, invasive procedures are required to confirm the diagnosis of IBD. Furthermore, the natural history of chronic IBD is characterised by an unpredictable variation in the degree of inflammation. Biological markers are needed to confirm remission, detect early relapses or local reactivation, and to monitor anti‐inflammatory therapies reliably. Whereas serum markers of inflammation are still not very helpful,^3,4,5 assays that determine intestinal inflammation by detecting neutrophil‐derived products in stool show great potential.⁶An important mechanism in the initiation and perturbation of inflammation in IBD is the activation of innate immune mechanisms.^7,8 Among the factors released by infiltrating neutrophils are proteins of the S100 family.^9,10 One example is calprotectin, which is detectable in the serum and stool during intestinal inflammation.¹¹ Calprotectin was initially described as a protein of 36 kDa, but was later characterised as a complex of two distinct S100 proteins, S100A8 and S100A9.^12,13,14 In recent years, calprotectin has been proposed as a faecal marker of gut inflammation reflecting the degree of phagocyte activation.^{6,15,16,17,18,19,20} Unfortunately, variation in faecal calprotectin assays still impedes the routine use of this marker as a sole parameter in clinical practice. The observed variation may be caused by the broad expression pattern of calprotectin, which is found in granulocytes as well as monocytes and is also inducible in epithelial cells.^21,22 In this context, the elevation in lactose intolerance is notable.^16,17,23S100A12 is more restricted to granulocytes. It is secreted by activated neutrophils and is abundant in the intestinal mucosa of patients with IBD.^9,24 Overexpression at the site of inflammation and correlation with disease activity in a variety of inflammatory disorders underscore the role of this granulocytic protein as a proinflammatory molecule.²⁵ The binding of S100A12 to the receptor for advanced glycation endproducts (RAGE) leads to the long‐term activation of nuclear factor kappa B, which promotes inflammation.²⁶ In mouse models of colitis, blocking the interaction of S100A12 with RAGE has been proved to attenuate inflammation. Data on murine models of colitis as well as human IBD point to an important role for S100A12 during the pathogenesis of these disorders.^9,26,27In a previous study, we demonstrated that S100A12 is overexpressed during chronic active IBD and serves as a useful serum marker for disease activity in patients with IBD.⁹ De Jong et al.²⁸ recently reported that S100A12 can be detected in the stool of children with Crohn''s disease. The aim of our present study was thus to analyse S100A12 in stool samples as well as its expression in the intestinal tissue of patients with confirmed IBD or IBS and in the stool of a normal control group. We correlated faecal S100A12 levels with endoscopic and histological findings in the same patients and investigated the diagnostic accuracy of S100A12 to detect intestinal inflammation.     

Clinical value of multidetector CT coronary angiography as a preoperative screening test before non-coronary cardiac surgery

Objective

Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non‐invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non‐coronary cardiac surgery.

Methods

132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for ⩾50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions ⩾50% at MDCTCA (Group 2) underwent CA.

Results

16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (⩾50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (>50% MDCTCA, <50% CA).No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1.

Conclusions

MDCTCA seems to be effective as a preoperative screening test prior to non‐coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.Since its introduction in the 1960s,¹ conventional coronary angiography (CA) has been considered the gold standard for the diagnosis of coronary artery disease because of its high contrast, temporal and spatial resolution.^2,3,4 In the past few years, we have witnessed a considerable increase in diagnostic and interventional procedures. Despite the high degree of accuracy (73–89%) of non‐invasive diagnostic tests such as exercise ECG, myocardial scintigraphy and stress‐echocardiography in detecting myocardial ischaemia,⁵ about 20% of patients undergoing CA due to a positive result of these non‐invasive tests, had no evidence of coronary lesions.^6,7Multidetector CT (MDCT), introduced into clinical practice in 2000, has demonstrated excellent technical characteristics for coronary artery evaluation. Results in the literature show a high degree of diagnostic accuracy in detecting significant coronary lesions and, particularly, an excellent capability of excluding them, due to negative predictive values ranging from 96 to 99%.^{8,9,10,11,12,13,14,15,16,17,18}Patients who are candidates for major non‐coronary cardiac or vascular surgery, such as heart valve replacement, aortic aneurysm and aortic dissection, require a complete assessment of potentially dangerous co‐morbidities. There is a 5 to 10% perioperative cardiac morbidity rate during vascular surgery, even in patients at low risk for coronary disease.¹⁹ According to Paul et al.²⁰ there is a 17% risk of severe multivessel disease in low clinical risk asymptomatic patients undergoing vascular surgery. American College of Cardiology/American Heart Association (ACC/AHA) guidelines for preoperative evaluation before major surgery recommend stratification of ischaemic heart disease with clinical and non‐invasive tests.^19,20,21,22 The diagnostic accuracy is 68 to 77% for exercise ECG and 73 to 85% for stress‐echocardiography. Myocardial scintigraphy provides an accuracy of 87–89% in patients with normal resting ECG, with a radiation exposure ranging from 4.6 to 20 mSv,²³ almost equivalent to MDCT coronary angiography (MDCTCA). However, for certain high‐risk patients, ACC guidelines suggest proceeding directly with coronary angiography rather than performing a non‐invasive test. Therefore, in clinical practice, CA is often performed before major vascular or cardiac surgery. Considering that millions of surgical procedures are probably performed every year worldwide (eg, 95 000 heart valve replacements/year in the USA),^6,7 several hundred thousand negative CAs are still performed.After some years of validation studies comparing MDCTCA with CA, studies on clinical utility are now warranted to demonstrate whether and how this technique can change and improve the current management of patients. The purpose of this study is to evaluate the clinical impact of MDCTCA as a preoperative screening test for cardiac risk assessment in patients who are candidates for major non‐coronary cardiac surgery and who are asymptomatic for ischaemic heart disease.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Design

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, and at 6 months and 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in one patient (5%) at the 6‐month, and in four patients (20%) at the 2‐year follow‐up evaluations. Frequencies of thrombus inside the SES at baseline, 6 months and 2 years did not differ one from another (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not a rare phenomenon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation shows that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore proposed the hypothesis that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides a direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. We herein present our findings as derived from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Methods

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, at 6 months and at 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (mean (SD) 1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in 5% of 6‐month, and in 20% of 2‐year follow‐up evaluations. The prevalence of thrombus inside the SES at baseline, 6 months and 2 years was similar (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not uncommon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation showed that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore suggested that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. Here we present our findings from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies

Objectives

To derive age and sex specific estimates of transition rates from advanced adenomas to colorectal cancer by combining data of a nationwide screening colonoscopy registry and national data on colorectal cancer (CRC) incidence.

Design

Registry based study.

Setting

National screening colonoscopy programme in Germany.

Patients

Participants of screening colonoscopy in 2003 and 2004 (n = 840 149).

Main outcome measures

Advanced adenoma prevalence, colorectal cancer incidence, annual and 10 year cumulative risk of developing CRC among carriers of advanced adenomas according to sex and age (range 55–80+ years)

Results

The age gradient is much stronger for CRC incidence than for advanced adenoma prevalence. As a result, projected annual transition rates from advanced adenomas to CRC strongly increase with age (from 2.6% in age group 55–59 years to 5.6% in age group ⩾80 years among women, and from 2.6% in age group 55–59 years to 5.1% in age group ⩾80 years among men). Projections of 10 year cumulative risk increase from 25.4% at age 55 years to 42.9% at age 80 years in women, and from 25.2% at age 55 years to 39.7% at age 80 years in men.

Conclusions

Advanced adenoma transition rates are similar in both sexes, but there is a strong age gradient for both sexes. Our estimates of transition rates in older age groups are in line with previous estimates derived from small case series in the pre‐colonoscopy era independent of age. However, our projections for younger age groups are considerably lower. These findings may have important implications for the design of CRC screening programmes.Most colorectal cancers (CRCs) develop from adenomas, among which “advanced” adenomas are considered to be the clinically relevant precursors of CRC. The natural history of colorectal adenomas is a decisive factor for the design of CRC screening measures and their cost effectiveness. Since advanced adenomas need to be removed once they are detected, any direct observation of their natural history would be unethical. Thus, available estimates for the progression of adenomas mostly stem from radiological surveillance data or from autopsy series collected prior to the colonoscopy era.^{1,2,3,4,5,6,7,8,9} However, these data are rather vague as they were derived from small and potentially selective samples. For example, a major source for the estimation of adenoma transition rates has been a retrospective review of Mayo Clinic records from 226 patients with colonic polyps ⩾10 mm in diameter in whom periodic radiographical examination of the colon was performed, and in whom 21 invasive carcinomas were identified during a mean follow up of 9 years.⁹ Despite the undoubted usefulness of available data sources from the pre‐colonoscopy era, sample size limitations did not allow reliable estimates of adenoma transition rates according to key factors, such as age and sex. Accordingly, a common estimate of these transition rates for all ages and both sexes has generally been assumed in previous studies on effectiveness and cost effectiveness of CRC screening.^{10,11,12,13,14,15,16,17} Given that sensitivity analyses in these studies showed that the advanced adenoma–carcinoma transition rate represents a very influential parameter,^10,11,13,18 its variation by age and sex might have a large impact on relative effectiveness and cost effectiveness of various screening schemes.The aim of this paper was to estimate risk for developing CRC according to age and sex among carriers of advanced adenomas by combining data from a large national colonoscopy screening database and national data on CRC incidence in Germany.     

Disease management programme for secondary prevention of coronary heart disease and heart failure in primary care: a cluster randomised controlled trial

Aims

To evaluate the effect of a disease management programme for patients with coronary heart disease (CHD) and chronic heart failure (CHF) in primary care.

Methods

A cluster randomised controlled trial of 1316 patients with CHD and CHF from 20 primary care practices in the UK was carried out. Care in the intervention practices was delivered by specialist nurses trained in the management of patients with CHD and CHF. Usual care was delivered by the primary healthcare team in the control practices.

Results

At follow up, significantly more patients with a history of myocardial infarction in the intervention group were prescribed a beta‐blocker compared to the control group (adjusted OR 1.43, 95% CI 1.19 to 1.99). Significantly more patients with CHD in the intervention group had adequate management of their blood pressure (<140/85 mm Hg) (OR 1.61, 95% CI 1.22 to 2.13) and their cholesterol (<5 mmol/l) (OR 1.58, 95% CI 1.05 to 2.37) compared to those in the control group. Significantly more patients with an unconfirmed diagnosis of CHF had a diagnosis of left ventricular systolic dysfunction confirmed (OR 4.69, 95% CI 1.88 to 11.66) or excluded (OR 3.80, 95% CI 1.50 to 9.64) in the intervention group compared to the control group. There were significant improvements in some quality‐of‐life measures in patients with CHD in the intervention group.

Conclusions

Disease management programmes can lead to improvements in the care of patients with CHD and presumed CHF in primary care.Cardiovascular diseases including coronary heart disease (CHD) and chronic heart failure (CHF) are the main cause of morbidity and mortality in most European countries.¹ Mortality from cardiovascular disease has declined over the last 30 years, a trend which has been attributed to secondary prevention therapies.^2,3 However, European surveys have shown considerable potential for improved levels of secondary prevention in people with established CHD.⁴ Studies in primary care, where most of these patients are managed, have also reported considerable potential to further increase secondary prevention through medical and lifestyle interventions.^5,6 “Medical” measures include aspirin therapy and blood pressure and lipid control, while “lifestyle” measures include increased exercise, dietary modification and smoking cessation.⁵ CHF is also a highly prevalent, chronic condition with high mortality and morbidity. It is increasing in prevalence and the public health burden from CHF is therefore likely to rise substantially over the next 10 years.⁷ The quality of life of patients with CHF is worse than for most chronic conditions managed in primary care and five‐year survival is worse than for many malignant conditions.⁸ However, appropriate treatment, including inhibitors of the renin‐angiotensin‐aldosterone system and beta‐blockers, has the potential to reduce hospitalisation and mortality in these patients.^9,10 The task of implementing a comprehensive package of effective measures for large numbers of patients has been described as daunting.⁵ It is therefore important to develop implementation strategies that are practical and effective. Many patients with CHF are incorrectly diagnosed and inadequately treated in primary care¹¹ and obstacles to appropriate primary care management include lack of knowledge, fear of complications with pharmacological treatments, lack of time and limited facilities for investigations.^12,13Systematic reviews indicate that secondary prevention programmes improve the process of care, reduce admissions to hospital and enhance quality of life or functional status in patients with CHD.¹⁴ Similarly, systematic reviews of disease management programmes in CHF suggest that specialised, multidisciplinary follow‐up can reduce hospitalisation and may lead to cost saving.^15,16,17 However, all the CHF trials included in these systematic reviews were conducted in highly specialised centres and recruited patients following discharge after hospitalisation. The applicability of the available CHF management programmes to countries with a primary care‐based healthcare system has therefore recently been questioned.¹⁸To achieve improved secondary prevention of CHD and CHF, primary care will need to adopt a systematic approach. Although disease management clinics for the management of CHD in primary care can improve patients'' outcomes,⁵ there are no such studies in the management of patients with CHF. Since the majority of patients with CHF will also have CHD,¹⁹ we investigated the effect of a disease management programme for patients with either or both conditions in primary care.     

A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study

Objective

To investigate risk factors for non‐Hodgkin''s lymphoma (NHL) and analyse NHL subtypes and characteristics in patients with systemic lupus erythematosus (SLE).

Methods

A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case control study on SLE patients who developed NHL during this observation period was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed. Tissue specimens on which the lymphoma diagnosis was based were retrieved and reclassified according to the WHO classification. NHLs of the subtype diffuse large B cell lymphoma (DLBCL) were subject to additional immunohistochemical staining using antibodies against bcl‐6, CD10 and IRF‐4 for further subclassification into germinal centre (GC) or non‐GC subtypes.

Results

16 patients with SLE had NHL, and the DLBCL subtype dominated (10 cases). The 5‐year overall survival and mean age at NHL diagnosis were comparable with NHL in the general population—50% and 61 years, respectively. Cyclophosphamide or azathioprine use did not elevate lymphoma risk, but the risk was elevated if haematological or sicca symptoms, or pulmonary involvement was present in the SLE disease. Two patients had DLBCL‐GC subtype and an excellent prognosis.

Conclusions

NHL in this national SLE cohort was predominated by the aggressive DLBCL subtype. The prognosis of NHL was comparable with that of the general lymphoma population. There were no indications of treatment‐induced lymphomas. Molecular subtyping could be a helpful tool to predict prognosis also in SLE patients with DLBCL.Evidence of an increased risk to develop haematological malignancy, and especially non‐Hodgkin''s lymphoma (NHL) in autoimmune diseases, has been gathered since the 1970s. First studies of Sjögren''s syndrome,¹ then rheumatoid arthritis (RA)² and now in the last decade studies from uni‐/multicentre SLE cohorts^3,4,5,6,7,8 and national SLE cohorts^9,10 have consistently shown a markedly increased risk of NHLs. As for NHL subtype, knowledge is more limited. RA and SLE share several disease manifestations like arthritis and “extra‐articular manifestations” such as serositis, sicca symptoms and interstitial inflammatory lung disease. In RA, a pronounced over‐representation of diffuse large B cell lymphoma (DLBCL) has been reported from a large population‐based cohort.¹¹ This lymphoma subtype was also the most frequent in an international multicentre study with lupus patients.¹² In Sjögren''s syndrome, approximately 85% are MALT lymphomas,¹³ although a recent study from a mono‐centre primary Sjögren''s syndrome cohort—with patients fulfilling the American–European Consensus Group criteria¹⁴—showed a predominance of DLBCL.¹⁵The pathophysiological mechanisms for the enhanced risk of developing NHL in patients with chronic inflammatory diseases are still not fully understood. Similarities of a variety of immunological disturbances that characterise both rheumatic conditions and lymphomas have been suggested as a linkage between these disorders as well as a possible potentiation of immunosuppressive drugs or certain viral infections, especially Epstein–Barr virus (EBV).^5,16Recently, advances in molecular characterisation have enabled more detailed subclassification of lymphomas based on the molecular expression of the tumour cells. For DLBCL, two prognostic groups have been identified among DLBCL in the general lymphoma population depending on the resemblance of gene expression profile with normal germinal centre (GC) or activated B cells by using global gene expression profiling^17,18 and immunophenotyping of tumour cells.^19,20 The GC DLBC lymphomas had a significantly better survival than those with non‐GC subtype.^17,18,19,20 No such subtyping has been reported in SLE patients.In a previous register study of a population‐based national Swedish SLE cohort, a threefold increased risk of lymphoma was found.¹⁰ This nested case‐control study focuses on those SLE patients that developed NHL. Information on clinical manifestations and pharmacological (cytotoxic) treatment of the SLE disease was retrieved from patient records. The lymphomas were re‐examined and reclassified, and DLBCLs were further divided into GC or non‐GC subtypes by immunohistochemistry. The presence of EBV in the lymphomas was also analysed.     

Persistent colonization and the spread of antibiotic resistance in nosocomial pathogens: resistance is a regional problem

Infections with antibiotic-resistant bacteria (ARB) in hospitalized patients are becoming increasingly frequent despite extensive infection-control efforts. Infections with ARB are most common in the intensive care units of tertiary-care hospitals, but the underlying cause of the increases may be a steady increase in the number of asymptomatic carriers entering hospitals. Carriers may shed ARB for years but remain undetected, transmitting ARB to others as they move among hospitals, long-term care facilities, and the community. We apply structured population models to explore the dynamics of ARB, addressing the following questions: (i) What is the relationship between the proportion of carriers admitted to a hospital, transmission, and the risk of infection with ARB? (ii) How do frequently hospitalized patients contribute to epidemics of ARB? (iii) How do transmission in the community, long-term care facilities, and hospitals interact to determine the proportion of the population that is carrying ARB? We offer an explanation for why ARB epidemics have fast and slow phases and why resistance may continue to increase despite infection-control efforts. To successfully manage ARB at tertiary-care hospitals, regional coordination of infection control may be necessary, including tracking asymptomatic carriers through health-care systems.Nosocomial infections with antibiotic-resistant bacteria (ARB) occur with alarming frequency (1), and new multidrug-resistant bacteria continue to emerge, including vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), two recent but isolated cases of vancomycin-resistant S. aureus (2, 3), and multiple-drug resistance in Gram-negative bacteria. In response, hospitals have used a variety of infection-control measures, some of which are costly and difficult to implement (4). Despite efforts to reduce transmission of ARB within hospitals, the incidence of VRE, MRSA, and other antibiotic-resistant infections continues to increase (1).An important distinction in the epidemiology of ARB is made between infection and colonization. Infection is characterized by serious illness when ARB contaminate wounds, the bloodstream, or other tissues. In contrast, colonization with ARB may occur in the gut, nasal cavities, or other body surfaces. Colonizing bacteria may persist for years without causing disease or harming their hosts (5, 6); we call such individuals carriers. These carriers increase colonization pressure; the number of patients who are shedding increases the risk that another patient becomes a carrier for ARB or acquires a resistant infection (7). Hospitals that reduce the incidence of resistance (the number of new cases) may see no reduction in overall prevalence (the fraction of patients with ARB), because these hospitals admit an increasing number of ARB carriers (8, 9). Patients infected with ARB generally remain hospitalized until the symptoms are cured, but they may continue to carry and shed ARB for months or years.We show that the prevalence of ARB in hospitals approaches equilibrium rapidly because of the rapid turnover of patients; the average length of stay (LOS) is ≈5 days (10, 11). Moreover, prevalence changes rapidly in response to changes in hospital infection control (11-17), so slow and steady increases in resistance must be due to something else, such as increases in the proportion of carriers admitted from the catchment population of a hospital, defined as the population from which patients are drawn, including long-term care facilities (LTCFs), other hospitals, and the community (5, 18). The health-care institutions that serve a common catchment population vary substantially in their relative size, transmission rates, and average LOS. How do increases in the number of ARB carriers in the catchment population contribute to increases in infections by ARB in the hospital, and what can be done about it?Mathematical models play an important role in understanding the spread of ARB (19). We have built on existing theory for the transmission dynamics of ARB developed for simple, well-mixed populations (12, 20), but we are focused on phenomena that occur at a large spatial scale, ignoring competition between sensitive and resistant bacteria and the biological cost of resistance (21) and the relationship between antibiotic use and the prevalence of ARB (11, 22, 23). We have developed mathematical models with multiple institutions connected by patient movement; such models are called “structured” populations or “metapopulations.” Thus, we are developing epidemiological models (20, 21, 24) focused specifically on the consequences of persistent colonization and population structure, applying existing theory for structured populations (20, 24-27).     

Colorectal Cancer Liver Metastasis Trends in the Kingdom of Saudi Arabia

Background/Aim:To elucidate colorectal cancer (CRC) disease patterns, demographics, characteristics, stage at presentation, metastases, and survival rates of patients, particularly those with liver metastases, at our center as the first report from the Kingdom of Saudi Arabia.Results:427 cases of CRC with a mean age at diagnosis of 55.47 ± 12.85 years, out of which 96% were resected. Stage II was predominant at presentation, followed by both stage III and IV, with the remainder being stage I. One hundred patients had distant metastases, of which the liver was the only location in 54 patients. Mean survival was 3.0 years. Overall survival rates for CRC patients with liver metastases who underwent resection were 30% at 2 years and 17% at 5 years, and the mean survival rate was 1.4 years.Conclusions:Both the mean survival rate of our CRC patients with resectable liver metastases and the 5-year survival rate of these patients are lower than global averages. This discrepancy is likely due to late diagnoses rather than more aggressive disease.Key Words: Colon cancer, metastasis, Saudi Arabia, survivalColorectal cancer (CRC) is considered to be the third most common malignancy worldwide.[1] It affects roughly 30–50 people per 100,000 individuals in the USA and Europe,[2] and roughly half of these patients develop metastases during the course of the disease.[3,4] The liver is the predominant site of metastasis in CRC, and 25% of patients present with metastases at the time of diagnosis (synchronous).[4,5,6] Throughout the course of the disease, in particular after resection of the primary tumor, approximately half of all CRC patients develop liver metastases.[4,5,6] CRC rates are markedly lower in Africa and the Middle East, occurring at an estimated rate of 3–11 per 100,000 individuals.[7] Specifically, in the Kingdom of Saudi Arabia (KSA), the incidence of CRC is increasing from 6.6 per 100,000 individuals in 2003[8] to over 12 per 100,000 individuals in 2008.[9]In a recent meta-analysis by Kanakas et al., the global 3 and 5-year mean survival rates of CRC were estimated to be 57.6 and 40.3%, respectively;[10] however, 5-year survival rates in the USA are estimated to be greater than 65%.[11] In comparison, the 5-year survival rate of CRC in the KSA is reported to be 44.6%.[12] Survival rates have improved tremendously for CRC due to early detection, application of total mesorectal excision, and addition of radiochemotherapy.[13,14] With respect to CRC patients with liver metastases, the estimated global mean 5-year survival is 38%, although this number varies dramatically from region to region.[10] Survival improvement for metastatic CRC is majorly due to the aggressive surgical approach in resecting all metastasis and the addition of effective systemic chemotherapy.[15] Despite increasing data pertaining to CRC incidence and survival in the KSA, information relating to the leading cause of death from this disease, namely liver metastasis, is currently scarce.[16] Therefore, the aim of this study is to elucidate CRC disease pattern and survival rates, particularly of patients with liver metastases, in the KSA population and to compare these figures to the global averages.     

Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis

Background/Aims

Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs are expressed in the gastrointestinal tract, their importance has so far been unclear. AQP3 is a water/glycerol transporter expressed at the basolateral membrane of colonic epithelial cells. The aim of this study was to investigate the involvement of AQP3 in enterocyte proliferation using mouse models of inflammatory bowel disease.

Methods

Expression and function of AQP3 in mouse colonic epithelium were established. Colitis was induced in wild‐type and AQP3 null mice by oral dextran sulphate administration or intracolonic acetic acid administration. Outcome measures included clinical disease severity, survival, pathology and cellular responses. Some mice were administered glycerol to test whether disease progression could be altered.

Results

AQP3 null mice given dextran sulphate developed severe colitis after 3 days, with colonic haemorrhage, marked epithelial cell loss and death. Wild‐type mice, which had comparable initial colonic damage as assessed by cell apoptosis, developed remarkably less severe colitis, surviving to >8 days. Cell proliferation was greatly reduced in AQP3 null mice. Oral glycerol administration significantly improved survival and reduced the severity of colitis in AQP3 null mice. Survival was also reduced in AQP3 null mice in the acetic acid model.

Conclusions

The results implicate a novel role for AQP3 in enterocyte proliferation that is probably related to its glycerol‐transporting function. AQP3 is thus a potential target for therapy of intestinal diseases associated with enterocyte destruction.The aquaporins (AQPs) are a family of water channels expressed in many epithelial, endothelial and other cell types. They facilitate transepithelial water transport in kidney tubules for urine concentration, and in glandular, choroidal and ciliary epithelia for fluid secretion.^1,2 AQPs in non‐epithelial tissues in the central nervous system and eye are also involved in the regulation of tissue hydration. Recently, analysis of transgenic mice lacking specific AQPs has revealed new cellular roles for AQPs that are unrelated to transcellular water transport.³ We found impaired angiogenesis in AQP1‐deficient mice as a consequence of reduced endothelial cell migration,⁴ which may be caused by slowed water movement into lamellipodia at the leading edge of migrating cells. A subset of AQPs (AQPs 3, 7 and 9), called ‘aquaglyceroporins'', transport water as well as glycerol, and possibly other small solutes. Mice lacking AQP3 have dry skin and delayed epidermal healing, with reduced glycerol content in epidermis and stratum corneum,^5,6 caused by impaired glycerol transport from the dermis through the normally AQP3‐expressing basal keratinocytes. Recent studies provided evidence for a new role for AQP3 in cell proliferation. Mice lacking AQP3 were found to have significantly impaired epidermal proliferation in a wound healing model,⁷ and impaired corneal epithelial cell proliferation after epithelial injury.⁸ Mice lacking AQP7 manifest age‐dependent adipocyte hypertrophy and glycerol accumulation,⁹ which we proposed is caused by reduced glycerol exit from the normally AQP7‐expressing adipocytes.AQPs are expressed strongly in gastrointestinal organs including the stomach (parietal cells), liver (hepatocytes and cholangiocytes), pancreas (acinar epithelia), gallbladder (epithelium), small intestine (lacteals, enterocytes) and colon (colonocytes).^10,11 Consequently, roles for AQPs in the secretion of bile and pancreatic fluid have been postulated, as well as in intestinal fluid absorption and secretion. However, phenotype analysis of AQP1, AQP4 and AQP8 knockout mice has revealed little or no consequence of AQP deletion on major gastrointestinal fluid‐transporting functions.^{12,13,14,15,16} The absence of overt gastrointestinal phenotypes in AQP‐deficient mice is surprising in view of the renal, central nervous system, ocular, glandular, cutaneous and other phenotypes found in these mice, particularly since the magnitude of gastrointestinal fluid transport is second only to that in kidney.The epithelium lining the intestine maintains its architecture by a balance between the continuous processes of epithelial cell generation from clonal stem cells¹⁷ at the base of intestinal crypts, and death of cells near the luminal surface. Recent evidence has suggested dysregulation of these processes in inflammatory bowel diseases (IBDs) such as ulcerative colitis, and has emphasised the importance of cell proliferation in disease progression.^18,19 There is evidence for a crucial role for Toll‐like receptor (TLR) signalling and commensal bacteria in the initiation and transduction of the inflammatory and tissue repair responses.^20,21 TLR‐4 null mice and related MyD88 null mice show significantly more severe disease progression in murine models of colitis as a result of impaired epithelial cell proliferation.²⁰Here, we present evidence for a new AQP function in the gastrointestinal tract. We found remarkably greater colonic pathology and mortality in mice lacking AQP3 than in wild‐type mice in experimental models of colitis, with impaired epithelial cell proliferation at the base of colonic crypts in the null mice. The motivations for this study included the strong expression of AQP3 in colonic epithelial cells that undergo rapid turnover,¹⁷ and, as mentioned above, the impairment of epidermal and corneal cell proliferation in AQP3 deficiency.^7,8 We used the dextran sulphate and intracolonic acetic acid models of colitis^21,22,23,24 to induce epithelial damage and restitution in the colon. The primary model used was the dextran sulphate model, a well‐described oral model of colitis. In order to verify the findings using a direct damage, non‐oral model, we also used intracolonic instillation of acetic acid.^25,26 Enterocyte turnover is strongly stimulated in these models, which we predicted could expose defects in enterocyte proliferation and/or migration in AQP3 deficiency. Consequences of the findings here include the potential involvement of AQP3 in epithelial cell proliferation in a variety of intestinal inflammatory diseases, and the possibility of new therapies based on pharmacological modulation of AQP3 expression.